1-(2-thenoyl)alkyl-4-aryl-1, 2, 3, 6-tetrahydropyridines



1-(2-THENOYL)ALKYL-4-ARYL-1,2,3,6-TETRA- HYDROPYRIDINES Paul Adriaan J.Janssen, Antwerpse Steenweg 16, Vosselaar, near Turnhout, Belgium NoDrawing. Filed Mar. 26, 1959, Ser. No. 801,992

' '5 Claims. (Cl. 260294".8) I

The present inventionrelates-to a new group of tetrahydropyridinederivatives and more particularly to 1-(2-thenoyl)alkyl-4-aryl-1,2,3,6-tetrahydropyridines of the generalstructural formula and the pharmaceutically useful non-toxic saltsthereof, wherein Ar is a monocyclic aryl radical, preferably of lessthan nine carbon atoms, and Alk is alower alkylene radical.

The radical Ar can represent halophenyl radicals such as fiuorophenyl,chlorophenyl, bromophenyl, and iodophenyl and monocyclic aromatichydrocarbon radicals such as phenyl, tolyl, and xylyl.

The radical Alk can represent a lower alkylene radical such asmethylene, ethylene, propylene, methylpropylene, tetramethylene,pentamethylene, and hexamethylene, but is preferably trimethylene.

The organic bases of thisinvention form pharmaceutically'acceptablenon-toxic salts with avariety ofinorganic and strong organic acidsincluding sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic,sulfamic, citric, lactic, maleic, malic, succinic, tartaric, cinnamic,acetic, benzoic, gluconic, ascorbic and related acids. They also formquaternary ammonium salts with a variety of organic esters of sulfuric,hydrohalic and aromatic sulfonic acids. Among such esters are methylchloride and bromide, ethyl chloride, propyl chloride, butyl chloride,isobutyl chloride, benzyl chloride and bromide, phenethyl bromide,naphthylmethyl chloride, dimethylsulfate, .diethyl sulfate, methylbenzenesulfonate, ethyl toluenesulfonate, ethylene chlorohydrin,propylene chlorohydrin, allyl bromide, methallyl bromide and crotylbromide.

The compounds of this invention can be prepared by the condensation ofan thenoylalkyl halide of the formula LS l-CO-Alk-Halogen with anappropriately selected 4-aryl-'1,2,3,6-tetrahydropyridine. The reactioncan be carried out in an inert solvent such as an aromatic hydrocarbon,e.g. benzene, toluene, xylene; a lower alkanol e.g. ethanol, propanol,butanol; and a lower alkanone, e.g. butanone, pentanone. The reactionrate can be accelerated by the use of elevated temperatures.

The compounds of this invention canalso be prepared by reacting anappropriately selected w-(4-aryl-l,2,3,6-tetrahydropyridine)alkanonitrile with a thenoyl magnesium halide,decomposing the complex, and recovering the product. Thew-(4-aryl-l,2,3,G-tetrahydropyridine) alkanonitrile required for thisreaction can be prepared by the condensation of a w-haloalkanonitrilewith an appropriately selected 4-aryl-l,2,3,6-tetrahydropyridine.

Alternatively, the compounds can be preparedby condensing a'thenoylhalide with the-sodium saltof analkyl United States Patent 2.acetoacetate to give the corresponding tic-thenoyl acetate ester, whichis then condensed with an appropriately selectedl-(w-haloalkyl)-4-aryl-1,2,3,6-tetrahydropyridine followed bysaponification and decarboxylation.

The thenoylalkyl halides used as intermediates can be convenientlyprepared by the Friedel-Crafts reaction, employing, for example,*y-chlOIObtltYlYl chloride and thio. phene. Mild Friedel-Craftsconditions can be used; thus a milder catalyst such as stannic chloridecan be used rather than aluminum chloride.

The intermediate 4-aryl-1,2,3,6-tetrahydropyridines can be convenientlyprepared by condensing a-methylstyrene, or an appropriately substitutedderivative, with ammonia and formaldehyde, followed by acid hydrolysis.

The compounds of this invention have useful pharmacological properties.They are depressants of the centralnervous system. In small doses theyexhibit marked tranquilizing effects. They are also anti-epileptic,antipyretic, hypnotic, and analygesic agents.

The compounds which constitute this invention and the methods for theirpreparation will appear more fully from a consideration of the followingexamples, which are given for the purpose of illustration only and arenot to be construed as limiting the invention in spirit or in scope. Inthese examples quantities areindicated as parts by weight. Temperaturesare expressedin degrees centigrade C.), and pressures are expressed inmillimeters of mercury (mm).

Example 1 A mixture of 84 parts of thiophene, 141 parts of'ychlorobutyryl chloride, and 870 parts of benzene is cooled to about 0C. While this temperature is maintained 260 parts of stannic chlorideare added over a 2 hour period. After the addition is completed, thecooling .bath is removed and the stirring is continued for about anhour. The reaction mixture is then poured into a mixture of 60 parts ofconcentrated hydrochloric acid and 450 parts of ice water. The organiclayer is sepa rated, washed with water, dried over anhydrous calciumchloride, and filtered. The filtrate is concentrated under reducedpressure. The residue is distilled to yield 2('y-chlorobutyryl)thiophene which boils at 144146 C. at 11 mm. ofpressure.

Example 2 A solution of parts of methyl bromide in 356 parts of ether isadded portionwise to a refluxing suspension of 24 pal-ts of magnesium in214 parts of ether. The mixture is refluxed for 2 hours, and then92-parts of p fluoroacetophenone are added in the course of 90 minutes.The refluxing is continued for 3 hours, after which the mixture isstirred for 24 hours. at room temperature. The Grignard complex isdestroyed by the addition of ammonium chloride and 10% hydrochloric acidsolution. The mixture is extracted with ether, and the ether extractsare washed with 10% sulfuric acid solution and then with water. Theextracts are dried over anhydrous calcium chloride, filtered, andconcentrated in vacuo to remove the solvent. About 0.5 part ofhydroquinone is added to the residue which is then heated to atemperature of -110 C. under apressure of 50 mm.. The distillate isextracted with ether and the ether extracts are dried over anhydrouscalcium chloride and filtered? A small quantity .of hydroquinone isadded to, the ether solution. The solution is fractionated bydi'stillatigd-to yield p-fluoro-a-methylsty-rene boiling at 9 3J-9. 4-Q.;-;at

'80 pressure.

'3000 parts of 36% formaldehyde is stirred and heateil'to Patented Feb.28, 1961 about 60 C. With cooling to maintain this temperature, 944parts of m-methylstyrene are added slowly. After the addition iscompleted, the mixture is stirred at room temperature until thetemperature of the reaction mixture drops to about 40 C. After 2000parts of methanol are added, the stirring is continued for 20 hours. Themethanol is removed in vacuo, and the residue is diluted with 3000 partsof concentrated hydrochloric acid. For 4 hours, the mixture is heatedwith stirring at a temperature of 100 C. The mixture is cooled, dilutedwith 2000 parts of water, and made alkaline with 15 normal sodiumhydroxide solution. The reaction mixture is extracted with benzene, andthe benzene extracts are dried over anhydrous potassium carbonate andfiltered. The benzene is removed from the filtrate. The remainingresidue is distilled in vacuo to yield 4-phenyl-1,2,3,6-tetrahydropyridine which boils at 97-112 C. at 1 mm.

pressure. 1

This base is dissolved in benzene. Dry, gaseous hydrogen chloride ispassed through the solution, whereupon there precipitates thehydrochloride which is collected on a filter. The4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride melts at about 199202C.

Example 4 Substitution of an equimolar amount of u-chloroacetyl chloridefor the 'y-ohlorobutyryl chloride in Example 1 yields the white,prismatic crystals of Z-(u-chlorOacetyD- thiophenc.

Substitution of an equimolar amount of m-bromoacetophenone for thep-fluoroacetophenone in Example 2 yields m-bromo-a-methylstyrene boilingat 99-102 C. at 11 mm. pressure.

Substitution of an equimolar amount of m-bromo-otmethylstyrene for thea-methylstyrene in Example 3 yields4-(m-bromophenyl)-1,2,3,6-tetrahydropyridine hydrochloride melting at261-267 C.

In a bomb a mixture of 13.2 parts of 2-(a-chloracetyl) thiophene, 36parts of 4-(m-bromophenyl)-1,2,3,6-tetrahydropyridine, and 0.1 part ofpotassium iodide in 120 parts of toluene is heated for 72 hours at atemperature of 145l50 C. The contents of the bomb are cooled Ichlorobutyryl chloride for the 'y-chlorobutyryl chloride and thenfiltered. The remaining solid is triturated with an equal parts mixtureof water and ether. The ether layer is separated and added to thefiltrate from the original reaction mixture. The combined solutions aredried over anhydrous potassium carbonate and filtered. Anhydroushydrogen chloride gas is passed through the solution. The solid thusprecipitated is recovered and recrystallized from a mixture of 2propanol and actone. In this manner there is obtained the hydrochlorideof 1 [a-2-thenoyl)methyl]-4-(m-bromophenyl) 1,2,3,6 tetrahydropyridinewhich is a white crystalline compound. The structural formula is Example5 In an open flask a mixture of 15.5 parts of 2-(chlorobutyryl)thiophene, 24 parts of 4-phenyl-l,2,3,6-tetrahydropyridine, and 0.1 part of potassium iodide in 100 parts oftoluene is heated under reflux for about 70 hours. The contents of theflask are cooled and then filtered. The solid residue is triturated witha mixture of 100 parts of water and 100 parts of ether. The ether layeris separated and added to the filtrate from the original reactionmixture. The combined solution is dried over anhydrous potassiumcarbonate and filtered. Dry, gaseous hydrogen chloride is introducedinto the solution. recrystallized from a mixture of 2-propanol andacetone :toyield the hydrochloride of l-[ -(z-thenoynpropyl] i- Theprecipitated salt is collected on a filter and in Example 1 yields thecolorless needles of Z-(B-methyl- 'y-chlorobutyDthiophene.

Substitution of 16.7 parts of Z-(B-methyl- -chlombutyryDthiophene forthe 2-(' -chlorobutyryl) thiophene in the preceding procedure yields thewhite, prismatic crystals of 1[/3-methyl-'y-(2-thenoyl)propyl]-4-phenyl-1, 2,3,6-tetrahydropyridinehydrochloride. 7

Example 6 Substitution of an equimolar amount of p-fiuoro-emethylstyrenefor the a-methylstyrene in Example 3 yields4-(p-fluorophenyl)-1,2,3,6-tetrahydropyridine boiling at 139-l41 C. at 4mm. pressure.

Substiution of 26.7 parts of 4-(p-fluorophenyl)-1,2,3,6-tetrahydropyridine in Example 5 yields 1- ['y-(2-thenoyl)-propyl]-4-(p-fluorophenyl)-1,2,3,6,tetrahydropyridine hydrochloridemelting at 178180.5 C.

Example 7 A solution of 192 parts of p-ehlorobromobenzene in 124 partsof ether is added dropwise to a suspension of 24 parts of magnesium in214 parts of ether. The mixture is refluxed for 2 hours. The mixture iscooled to about 5 C., and 39 parts of acetone are added in the course of2 hours. The mixture is stirred for 24 hours at room temperature andthen decomposed with ammonium chloride solution and 10% hydrochloricacid. The solution is extracted with 'ether. washed with 10% sulfuricacid and then with water. This solution is dried over anhydrous calciumchloride, filtered, and concentrated in vacuo. The residual carbinol isheated under reduced pressure of about 50 mm. in the presence of 0.5part of hydroquinone for 2 hours on an oil bath at a temperature of -110C. The styrene and water are distilled ofi. The product is extractedwith ether. The ether extract is dried over anhydrous calcium chloride,filtered, and fractionated over hydroquinone to yieldp-chloro-wmethylstyrene boiling at 8385' C. at 15 mm. pressure.

Substitution of an equimolar amount of p-chloroot-methylstyrene for thea -methylstyre'ne in Example 3 yields4-(p-ch1or'opheny1)-1,2,3,6-tetrahydropyridine boiling at 157l60 C. at 8mm. pressure.

Substitution of 293 parts of 4(p-chlorophenyl)-1,2,3,6-tetrahydropyridine for the 4-phenyl-1,2,3,6-tetrahydropyridinein Example 5 yields l-['y-(2-thenoyl)- 'propyl]-4-(p-chlorophenyl)1,2,3,6 tetrahydropyridine hydrochloride melting at207-208.5 C.

Example 8 Example 9 Substitution of an equimolar amount ofo,p-dimethylacetophenone for the p-fiuoroacetophenone in Example 2yields o,p-dimethyl-u-methylstyrene boiling at 79-83 C. at 17 mm.pressure. 7

Substitution of an equimolar amount of o,p-dimethylc-methylstyrene forthe a-methylstyrene in Example? The ether layer is Substitution of anequimolar amount of p-bromoacetophenone for the p-fluoroacetophenone inExample 2 yields p-bromo-u-methylstyrene boiling at 103-l06 C. at 15 mm.pressure.

Substitution of an equimolar amount of p-bromo-amethylstyrene for thea-methylstyrene in Example 3 yields4-(p-bromophenyl)-l,2,3,6-tetrahydropyridine hydrochloride melting at243.5-245 C.

Substitution of 36 parts of 4-(p-bromophenyl)-1,2,3,6-tetrahydropyridine for the 4-phenyl-l,2,3,6-tetrahydropyridine inExample 5 yields 1-['y-(2-thenoyl)propyl]-4- (p-bromophenyl)-1,2,3,6tetrahydropyridine hydrochloride melting at 218-220 C.

Example 11 Substitution of an equimolar amount of fi-chlorovalerylchloride for the 'y-chlorobutyryl chloride in Example 1 6 yields thecolorless needles of 1-[6-(2-thenoyl)butyl]-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride.

What is claimed is: 1. A compound of the formula wherein Ar is a memberof the class consisting of phenyl, halophenyl, tolyl, and xylyl, andwherein Alk is lower alkylenc.

2. A compound of the formula Halogen References Cited in the file ofthis patent Levine et al.: Chem. Abstracts, vol. 47, col. 8077 (1953).

1. A COMPOUND OF THE FORMULA